6-Chloro-2,4-pyrimidine-dicarbamate-3-oxides

ABSTRACT

Oxadiazolopyrimidine derivatives of the formula ##STR1## wherein R and R 1  are as hereinafter described, prepared, inter alia, by cyclizing a compound of the formula ##STR2## wherein R and R 1  are as hereinafter described. The end products are useful in the treatment of vascular-conditioned hypertension or as vasodilators in the case of peripheral blood supply disorders.

This is a division of application Ser. No. 873,183, filed Jan. 27, 1978,U.S. Pat. No. 4,150,131.

BRIEF SUMMARY OF THE INVENTION

The invention relates to oxadiazolopyrimidines characterized by theformula ##STR3## wherein R is alkyl, alkoxyalkyl, haloalkyl, aralkyl oraryl, and R₁ is dialkylamino, 4-alkyl-1,2,5,6-tetrahydropyridin-1-yl,piperidino, azabicyclononyl, azabicyclooctyl, 3-pyrrolin-1-yl,3-hydroxy-1-piperidinyl or 4-hydroxy-1-piperidinyl or, when R ishaloalkyl, aralkyl or aryl, R₁ can also be1,2,5,6-tetrahydropyridin-1-yl,

and salts thereof with pharmaceutically acceptable bases.

DETAILED DESCRIPTION OF THE INVENTION

The oxadiazolopyrimidine derivatives of the invention are characterizedby the formula ##STR4## wherein R is alkyl, alkoxyalkyl, haloalkyl,aralkyl or aryl, and R₁ is dialkylamino,4-alkyl-1,2,5,6-tetrahydropyridin-1-yl, piperidino, azabicyclononyl,azabicyclooctyl, 3-pyrrolin-1-yl, 3-hydroxy-1-piperidinyl or4-hydroxy-1-piperidinyl, or when R is haloalkyl, aralkyl or aryl, R₁ canalso be 1,2,5,6-tetrahydropyridin-1-yl,

or a salt thereof with a pharmaceutically acceptable base.

The term "alkyl" used herein, alone or in combination, denotesstraight-chain and branched-chain saturated hydrocarbon groupscontaining 1-8 carbon atoms such as, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl and the like. Theterm "alkoxy" denotes alkyl ether groups in which the "alkyl" moiety isas earlier described. The term "haloalkyl" denotes alkyl groups in whichone or more of the hydrogen atoms has been replaced by "halogen". Theterm "halogen" denotes fluorine, chlorine, bromine or iodine. The term"aryl" denotes a mononuclear or dinuclear aromatic group containing upto 12 carbon atoms in which one or more of the hydrogen atoms can bereplaced by alkyl, alkoxy or halogen such as, for example, phenyl,halophenyl, methoxyphenyl, naphthyl and the like. The term "aralkyl"means an arylalkyl group such as benzyl, phenethyl and the like.

Preferred compounds of formula I are those in which R is alkyl,especially alkyl containing 1-4 carbon atoms. Furthermore, compounds offormula I wherein R₁ is piperidino or azabicyclononyl, preferably3-azabicyclo[3.2.2]non-3-yl, are also preferred. Especially preferredare compounds of formula I wherein R₁ is piperidino.

From the foregoing it will be appreciated that those compounds offormula I wherein R is alkyl containing 1-4 carbon atoms and R₁ ispiperidino or 3-azabicyclo[3.2.2]non-3-yl are especially preferred.

Especially preferred compounds of formula I are:

Methyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate;

Isobutyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate;and

Butyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate.

According to the process of the invention, the oxadiazolopyrimidinederivatives (i.e., the compounds of formula I and their salts) can beprepared by

(a) cyclizing a compound of the formula ##STR5## wherein R and R₁ are aspreviously described, or

(b) trans-esterifying a compound of formula I with an alcohol of theformula

    R'--OH

wherein R' is alkyl, alkoxyalkyl, haloalkyl, aralkyl or aryl, but isdifferent from R,

to give a compound of the formula ##STR6## wherein R' is as previouslydescribed, and, if desired,

(c) converting a resulting compound of formula I into a salt orconverting a salt into a different salt.

The cyclization of a compound of formula II is carried out in a mannerknown per se by heating to a temperature in the range of from about 50°C. to about 200° C., preferably between about 100° C. and 150° C. Thecyclization can be carried out in the absence or presence of a solventor solvent mixture. If the cyclization is carried out in the presence ofa solvent or solvent mixture, then there can be used as the solventaromatic hydrocarbons such as benzene, toluene or xylene, chlorinatedhydrocarbons such as chloroform, alcohols such as butanol or isobutanol,ethers such as dibutyl ether, dioxane or diethyleneglycol dimethylether, dimethylformamide, dimethylsulfoxide and the like or mixturesthereof.

It will be appreciated that there can either be used a solvent whoseboiling point lies higher than the cyclization temperature, or thatthere can be used a solvent boiling in the temperature range mentionedearlier at its reflux temperature. The cyclization is preferably carriedout using dimethylformamide or toluene as the solvent. The cyclizationtime depends on the temperature at which the cyclization is carried outand lies in the range of from about 0.25 hour to about 18 hours. If thecyclization is carried out at a temperature in the preferred temperaturerange of from about 100° C. to about 150° C., then the cyclization timeis in the range of from about 0.25 hour to about 12 hours, preferably0.25 hour to 2 hours. When an alcohol is used as the solvent, then itwill be appreciated that, if a trans-esterification is to be avoided,the alcohol must yield a radical which corresponds to that present inthe starting material utilized.

In another especially preferred embodiment, the cyclization is carriedout in the presence of a base, in which case the temperature can be heldsubstantially lower. In this embodiment, the cyclization is preferablycarried out at a temperature in the range of from about 0° C. to about80° C., conveniently at room temperature. Suitable bases are inorganicbases, for example, alkali hydroxides such as sodium hydroxide andpotassium hydroxide; alkaline earth hydroxides such as barium hydroxideand calcium hydroxide; carbonates such as potassium carbonate and sodiumcarbonate, and bicarbonates such as sodium bicarbonate; and organicbases such as dimethylamine, triethylamine, ethyldiisopropylamine andthe like. When a base is used, the cyclization is carried out in asuitable inert solvent or solvent mixture. As the solvent there can beutilized a solvent referred to hereinbefore. When an inorganic base isused, the cyclization is conveniently carried out in a water-containingsolvent mixture or in the presence of water in a two-phase system suchas, for example, methylene chloride/water. When it is desired to bringabout an intentional trans-esterification, the cyclization is preferablycarried out in the presence of a base.

The trans-esterification of a compound of formula I is carried out in aknown manner by reacting a compound of formula I with an appropriatealcohol at a temperature in the range of from about 25° C. to about 150°C. The trans-esterification is preferably carried out in the presence ofa base. Suitable bases for this purpose are alkali alcoholates, alkalihydroxides, carbonates, and the like. It will be appreciated that whenan alcoholate is used, this corresponds to the alcohol utilized. Thetrans-esterification is carried out in an inert organic solvent, forexample, an aromatic hydrocarbon such as benzene or xylene, an ethersuch as dioxane, tetrahydrofuran or ethyleneglycol dimethyl ether,dimethylformamide, dimethylsulfoxide, and the like. If the alcohol usedis liquid at the reaction temperature, then the excess alcohol can alsoserve as the reaction medium.

The starting materials of formula II are novel and also form part of thepresent invention. The compounds of formula II can be prepared, forexample, by reacting a compound of formula III or a tautomer thereof offormula IV or V ##STR7## wherein R₁ is as previously described, with achloroformic acid ester of the formula

    Cl--COOR                                                   VI

wherein R is as previously described.

The reaction of a compound of formula III or of a tautomer thereof offormula IV or V with a chloroformic acid ester of formula VI is carriedout in an inert solvent or solvent mixture and in the presence of anacid binding agent. Suitable solvents for the present purpose arechlorinated hydrocarbons such as methylene chloride and chloroform,ethers such as diethyl ether, tetrahydrofuran and dioxane,dimethylformamide, and the like, or mixtures thereof. The reaction canalso be carried out in a water-containing solvent or in the presence ofwater in a two-phase system such as, for example, methylenechloride/water. Examples of acid binding agents are bases such astriethylamine, ethyldiisopropylamine, dimethylamine, pyridine, alkalihydroxides and the like. When the reaction is carried out in thepresence of a liquid base, then this can also serve as the solvent. Thereaction is conveniently carried out at a temperature in the range offrom about -10° C. to room temperature, preferably between about 0° C.and 10° C.

Alternatively, the starting materials of formula II can also be preparedby reacting a 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide of the formula##STR8## wherein R is as previously described, with an amine of theformula

    R.sub.1 H                                                  VIII

wherein R₁ is as previously described.

The reaction of a 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide of formulaVII with an amine of formula VIII is carried out in an inert solvent orsolvent mixture. Suitable solvents for the present purpose arechlorinated hydrocarbons such as methylene chloride and chloroform,aromatic hydrocarbons such as toluene and xylene and the like ormixtures thereof. The reaction is preferably carried out under theatmosphere of an inert gas, preferably argon or nitrogen, at atemperature in the range of from about 0° C. to about 50° C., preferablyat room temperature. In place of an inert solvent there can also be usedan excess of amine of formula VIII. The starting materials of formula IIwherein R₁ is 3-hydroxy-1-piperidinyl or 4-hydroxy-1-piperidinyl arepreferably prepared according to this alternative procedure, because, inthe case of processes starting from compounds of formula III ortautomers thereof of formulas IV and V, the hydroxy group may also becarbamoylated, which, of course, would reduce the yield of the desiredstarting material of formula II.

The compounds of formula III and their tautomers of formulas IV and Vare known or can be prepared in analogy to the preparation of knowncompounds.

The compounds of formula VII are novel and can be prepared by reacting2,4-diamino-6-chloropyrimidine-3-oxide of the formula ##STR9## with achloroformic acid ester of formula VI hereinbefore.

The reaction of 2,4-diamino-6-chloropyrimidine-3-oxide of formula IXwith a chloroformic acid ester of formula VI is carried out under theconditions described hereinbefore for the reaction of a compound offormula III or a tautomer thereof of formula IV or V with a chloroformicacid ester of formula VI.

The compounds of formula I can be converted into salts, for example, bytreatment with an inorganic base such as an alkali hydroxide, forexample, sodium hydroxide or potassium hydroxide; an alkaline earthhydroxide, for example, calcium hydroxide; or with an organic base, forexample, a monoalkylamine such as methylamine, a dialkylamine such asdimethylamine, a trialkylamine such as triethylamine; a basic amino acidsuch as arginine; piperidine; an azabicyclooctane or -nonane, such as3-azabicyclo[3.2.1]octane or 3-azabicyclo[3.2.2]nonane, or the like.Salts of the compounds of formula I can also be prepared bydouble-decomposition of a suitable salt. The pharmaceutically acceptablesalts of the compounds of formula I are preferred.

The oxadiazolopyrimidine derivatives provided by the present inventionpossess long-lasting valuable vasodilating and/or bloodpressure-lowering properties and can accordingly be used for thetreatment of vascular-conditioned hypertensions and also as vasodilatorsin the case of peripheral blood supply disorders.

The blood pressure-lowering activity can be determined in conscious,spontaneous hypertensive rats by the following method:

The systolic blood pressure and the heart frequency are measured twicebefore administration of the test substance. The test substance isadministered by means of an oesophageal probe twice daily, morning andafternoon. Both parameters are measured 1, 3, 6 and 24 hours after theadministration and the percentage variations to the control values arecalculated. The systolic blood pressure is measured indirectly in thetail artery of the rat by the method of Gerold et al. (Helv. Physiol.Acta 24: 58-69, 1966; Arzneimittelforschung 18: 1285-1287, 1968).

The results obtained are complied in the Table which follows. In eachcase, the maximum percentage deviation from the control values as wellas the duration of activity in hours calculated as the average valuefrom 5 experiments, are given.

    ______________________________________                                                    Blood pressure                                                                            Heart frequency                                                                Duration of   Duration of                                    Dosage           activity      activity                               Compound                                                                              mg/kg p.o.                                                                              Δ%                                                                             in hours Δ%                                                                           in hours                               ______________________________________                                        A       3         -26    >24      +15  >24                                            10        -35    >24      +20  >24                                    B       1         -11    >24      - 5  >24                                            10        -32    >24      +21  >24                                    C       3         -22    >24      -15  >24                                            10        -29    >24      +13  >24                                    D       10        -15    >24      +12  6                                      E       10        -8     <24      -6   <24                                            30        -18    >24      +10  6                                      ______________________________________                                         A=Ethyl                                                                       B=Isobutyl                                                                    5piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3apyridimine-7-carbamate-            C=Butyl 5piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3apyrimidine-7-carbamate     D=Ethyl                                                                       5[3azabicyclo[3.2.2]non3-yl2-oxo-2H-[1,2,4oxadiazolo[2,3a]pyrimidine7-car    amate                                                                          E=Benzyl                                                                      5[3,6dihydro-1(2H)-pyridyl2-oxo-2H-[1,2,4oxadiazolo[2,3a]pyrimidine7-carb    mate                                                                      

The compounds of formula I and their pharmaceutically acceptable saltscan be used as medicaments; for example, in the form of pharmaceuticalpreparations which contain them in association with a compatiblepharmaceutical carrier material. The carrier material can be an organicor inorganic inert carrier material suitable for enteral or parenteraladministration, for example, water, gelatin, gum arabic, lactose,starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols,or the like. The pharmaceutical preparations can be made up in solidform, for example, as tablets, dragees, suppositories or capsules, or inliquid form, for example, as solutions, suspensions or emulsions. Thepharmaceutical preparations may be sterilized and/or may containadjuvants such as preserving, stabilizing, wetting or emulsifyingagents, salts for varying the osmotic pressure or buffers. Thepharmaceutical preparations can also contain still other therapeuticallyvaluable substances.

The daily dosage of a compound of formula I in the case of oraladministration can comprise from about 10 to about 500 mg. and in thecase of intravenous administration from about 1 to about 50 mg. It willbe appreciated, however, that the aforementioned dosages are given byway of example only and can be varied according to the severity of thecondition to be treated and according to the judgment of the personadministering a compound of formula I.

The following Examples illustrate the process provided by the presentinvention. The melting points given in the Examples are not corrected.

EXAMPLE 1 Preparation of pure ethyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate

4.5 G. of diethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide aretreated under an argon atmosphere with 60 ml. of toluene and the mixtureis heated to reflux for 12 hours. After cooling the mixture, theprecipitate is filtered off and recrystallized from ether, there beingobtained pure ethyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 209°-210° C. (decomposition).

In an analogous manner,

from 4 g. of diisobutyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide,there was obtained isobutyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 188°-190° C.;

from 10.6 g. of dibutyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide,there was obtained butyl5-piperidino-2-oxo-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 187°-190° C.; and

from 12 g. of dibenzyl6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, therewas obtained benzyl5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo-[2,3-a]pyrimidine-7-carbamate,having a melting point of 218° C.

The diethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide used as thestarting material can be prepared as follows:

8 G. of 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidino-1-pyrimidinein 100 ml. of methylene chloride and 20 ml. of triethylamine are cooledto 5° C. while stirring. The mixture is treated with 20 ml. ofchloroformic acid ethyl ester. The mixture is stirred at 5° C. for 30minutes and then at room temperature for 18 hours. The mixture isextracted with 100 ml. of methylene chloride, washed with 50 ml. ofwater, dried over magnesium sulfate and evaporated under reducedpressure. Recrystallization of the residue from methylene chloride/etheryields diethyl 6-piperidino-2,4-pyrimidinedicarbamate-3-oxide, having amelting point of 161°-162° C.

In an analogous manner,

using chloroformic acid butyl ester, there is obtained dibutyl6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide, having a melting pointof 187°-190° C.; and

using chloroformic acid isobutyl ester there is obtained diisobutyl6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide, having a melting pointof 138°-139° C.

The dibenzyl6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxidelikewise used as the starting material can be prepared as follows:

(A) 144.5 G. of 2,4-diamino-6-chloropyrimidine are suspended in 2000 ml.of ethanol. The suspension is warmed to 35° C. while stirring (about 15minutes), the greater part of the material passing into solution. Thismixture is then cooled down to 6°-8° C. and at this temperature thereare added dropwise within 40 minutes 175 ml. of 40% peracetic acid inglacial acetic acid. After completion of the addition, the mixture isstirred at 6°-8° C. for a further 30 minutes. Thereafter, the mixture isleft to warm up to room temperature, and stirred at this temperature for3 hours. 2000 Ml. of petroleum ether are added, the mixture is stirredfor 1 hour and then left to stand overnight. The separated precipitateis filtered off, back-washed with 200 ml. of petroleum ether and driedunder reduced pressure, there being obtained2,4-diamino-6-chloro-pyrimidine-3-oxide. Recrystallization yieldsanalytically pure product having a melting point of 193° C.

(B) 75 G. of 2,4-diamino-6-chloropyrimidine are dissolved at 35° C. in1500 ml. of ethanol. The solution is cooled to -10° C. and a solution of100 g. of 3-chloroperbenzoic acid in 500 ml. of ethanol is slowly addeddropwise within 1 hour. The suspension is subsequently stirred at -10°C. for 7 hours and left to stand at 5° C. overnight. The suspension isneutralized with 24 g. of sodium hydroxide in 100 ml. of water. Thesolid material is filtered off and recrystallized from ethanol, therebeing obtained pure 2,4-diamino-6-chloropyrimidine-3-oxide.

155 G. of 2,4-diamino-6-chloropyrimidine-3-oxide are mixed under anargon atmosphere with 640 ml. of o-xylene and 260 ml. of1,2,5,6-tetrahydropyridine and the mixture is stirred. The mixture isthen heated to reflux for 30 minutes, the internal temperature risingfrom 115° C. to 123° C. The mixture is then cooled to 5° C., treatedwith 40 g. of sodium hydroxide in 400 ml. of water and stirred at 5° C.for 1 hour. The precipitate formed is filtered off, washed with 200 ml.of water and recrystallized from 3000 ml. of water, there being obtainedpure 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide, havinga melting point of 263°-265° C. (decomposition).

20 G. of 2,4-diamino-6-[2,3-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide aresuspended in 250 ml. of methylene chloride and 50 ml. ofN-ethyldiisopropylamine and the mixture is cooled down to 5° C. 50 Ml.of chloroformic acid benzyl ester are added dropwise within 30 minutesand the mixture is then further stirred at room temperature for 15hours. 200 Ml. of water are then added dropwise, the two phases areseparated and the aqueous phase is extracted with methylene chloride.The organic phases are combined, dried over potassium carbonate andevaporated at 30° C. under reduced pressure. The residue isrecrystallized from ether/ethanol, there being obtained dibenzyl6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, havinga melting point of 172° C.

EXAMPLE 2 Preparation of pure ethyl5-dimethylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate

1 G. of diethyl 6-dimethylamino-2,4-pyrimidine-dicarbamate-3-oxide isheated to 140° C. for 30 minutes in 10 ml. of N,N-dimethylformamideunder an argon atmosphere. The solution is cooled and the solvent isevaporated under reduced pressure. The crystalline residue isrecrystallized from methylene chloride/ethanol, there being obtainedpure ethyl5-dimethylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 230°-240° C.

The diethyl 6-dimethylamino-2,4-pyrimidine-dicarbamate-3-oxide used asthe starting material can be prepared as follows:

4 G. of6-amino-1,2-dihydro-1-hydroxy-2-imino-4-dimethylamino-1-pyrimidine in100 ml. of methylene chloride and 15 ml. of triethylamine are cooled to5° C. while stirring. The mixture is treated with 10 ml. of chloroformicacid ethyl ester and stirred at room temperature for 16 hours. Themixture is subsequently extracted with 100 ml. of methylene chloride,washed with 60 ml. of water, dried over potassium carbonate andevaporated under reduced pressure. The residue is recrystallized fromether, there being obtained diethyl6-dimethylamino-2,4-pyrimidine-dicarbamate-3-oxide, having a meltingpoint of 237°-238° C.

EXAMPLE 3 Preparation of ethyl5-{3-azabicyclo[3.2.2]non-3-yl}-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate

4.1 G. of diethyl6-{3-azabicyclo[3.2.2]non-3-yl}-2,4-pyrimidine-dicarbamate-3-oxide aresuspended in 50 ml. of dimethylformamide and warmed to 140° C. for 30minutes under an argon atmosphere. After cooling the solution, thedimethylformamide is distilled off under reduced pressure and theresidue is filtered over silica gel. Elution with chloroform and ethanolyields ethyl5-{3-azabicyclo[3.2.2]non-3-yl}-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 210°-215° C. (decomposition). Analyticallypure product is obtained by recrystallization from methylenechloride/ether.

The diethyl6-{3-azabicyclo[3.2.2]non-3-yl}-2,4-pyrimidine-dicarbamate-3-oxide usedas the starting material can be prepared as follows:

4 G. of3-(2',4'-diamino-6'-pyrimidinyl)-3-azabicyclo[3.2.2]nonan-3'-oxide arecooled to 5° C. while stirring in 150 ml. of methylene chloride and 10ml. of triethylamine. The mixture is then treated with 8 ml. ofchloroformic acid ethyl ester, stirred at 5° C. for 30 minutes andsubsequently at room temperature overnight. The solution is washed with120 ml. of water, extracted with 200 ml. of methylene chloride, driedover potassium carbonate and evaporated under reduced pressure.Recrystallization of the residue from methylene chloride/ether yieldsdiethyl6-{3-azabicyclo[3.2.2]non-3-yl}-2,4-pyrimidine-dicarbamate-3-oxide,having a melting point of 158° C.

EXAMPLE 4 Preparation of (2-trichloroethyl)5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate

10 G. of bis(2-trichloroethyl)6-[3,6-dihydro-1(2H)-pyridyl]-pyrimidine-dicarbamate-3-oxide are heatedto 120° C. for 20 minutes under an argon atmosphere in 100 ml. ofdimethylformamide. The solution is then evaporated under reducedpressure and the residue is chromatographed, there being obtained(2-trichloroethyl)5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 205°-207° C. (decomposition).

The starting material can be prepared as follows:

10 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-pyrimidine-3-oxideare suspended in 100 ml. of methylene chloride and 20 ml. ofethyldiisopropylamine. The suspension is cooled to 0° C. and, whilestirring, there are added dropwise 20 ml. of chloroformic acidtrichloroethyl ester. The mixture is then stirred at 5° C. for 3 hours.Subsequently, 100 ml. of water are cautiously added dropwise. Themixture is extracted with methylene chloride. The organic phases aredried over magnesium sulfate and the solvent is distilled off underreduced pressure. The residue is recrystallized from ethanol, therebeing obtained pure bis(2-trichloroethyl)6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, havinga melting point of 210° C. (decomposition).

EXAMPLE 5 Preparation of pure methyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate

5 G. of dimethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide aredissolved in 200 ml. of methylene chloride and mixed with 100 ml. ofwater. While stirring vigorously, the mixture is adjusted withconcentrated sodium hydroxide to pH 12.5 and stirred at this pH for 3hours. The two phases are separated and the aqueous phase is adjusted topH 4 with concentrated hydrochloric acid. The resulting whiteprecipitate is filtered off, washed with water, pre-dried slightly andrecrystallized from a mixture of methylene chloride and methanol, therebeing obtained pure methyl5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 210°-214° C. (decomposition).

The starting material can be prepared as follows:

56 G. of 2,4-diamino-6-chloropyrimidine-3-oxide in 500 ml. ofdimethylformamide and 100 ml. of triethylamine are cooled to 0° C. 80Ml. of chloroformic acid methyl ester are added dropwise while stirringwith 1 hour. After completion of the addition, the mixture is stirredfor 48 hours. The precipitate is filtered off, suspended in a mixture of2500 ml. of methylene chloride and 500 ml. of methanol and stirred for80 minutes. The insoluble residue is filtered off and dried, there beingobtained pure dimethyl 6-chloro-2,4-pyrimidine-dicarbamate-3-oxide,having a melting point of 204° C. (decomposition). The organic phase iswashed with water and concentrated, there being obtained a furtheramount of pure material.

A suspension of 7.5 g. of dimethyl6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 35 ml. of methylenechloride is treated with 14.5 ml. of piperidine and the mixture isstirred at room temperature under an argon atmosphere for 18 hours. Thewhite precipitate formed is filtered off and recrystallized from amixture of methylene chloride and methanol, there being obtained puredimethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide, having amelting point of 202° C. (decomposition).

EXAMPLE 6 Preparation of pure methyl5-(3-pyrrolin-1-yl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate

4.5 G. of dimethyl6-(3-pyrrolin-1-yl)-2,4-pyrimidine-dicarbamate-3-oxide are suspended ina mixture of 200 ml. of methylene chloride and 200 ml. of water. Thesuspension is adjusted with concentrated sodium hydroxide to pH 12.5 andstirred at this pH for 3 hours. The two phases are then separated andthe aqueous phase is adjusted to pH 3 with concentrated hydrochloricacid. The separated white precipitate is filtered off, pre-dried andrecrystallized from a mixture of methylene chloride and methanol, therebeing obtained pure methyl5-(3-pyrrolin-1-yl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 230°-234° C. (decomposition).

The starting material can be prepared as follows:

A suspension of 12.5 g. of dimethyl6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 100 ml. of methylenechloride is treated with 15 g. of 3-pyrroline and the mixture is stirredat room temperature under an argon atmosphere for 26 hours. The whiteprecipitate formed is filtered off and recrystallized from a mixture ofmethylene chloride and methanol, there being obtained pure dimethyl6-(3-pyrrolin-1-yl)-2,4-pyrimidine-dicarbamate-3-oxide, having a meltingpoint of 206° C. (decomposition).

EXAMPLE 7 Preparation of pure methylracemic-5-(4-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate

3.1 G. of dimethylracemic-6-(4-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxideare suspended in 100 ml. of methylene chloride and 100 ml. of water. Thesuspension is adjusted with concentrated sodium hydroxide to pH 12.6 andstirred at this pH for 3.5 hours. The two phases are then separated andthe aqueous phase is adjusted to pH 3.2 with concentrated hydrochloricacid solution. The separated white precipitate is filtered off,pre-dried and recrystallized from methylene chloride and methanol, therebeing obtained pure methylracemic-5-(4-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 250°-260° C. (decomposition).

The starting material can be prepared as follows:

A suspension of 2.5 g. of dimethyl6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 100 ml. of methylenechloride is treated with 10 g. of 4-hydroxy-piperidine and stirred atroom temperature under an argon atmosphere for 70 hours. The separatedprecipitate is filtered off and recrystallized from a mixture ofmethylene chloride and methanol, there being obtained pure dimethylracemic-6-(4-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide,having a melting point of 265°-266° C.

EXAMPLE 8 Preparation of pure methylracemic-5-(3-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate

5.6 G. of dimethylracemic-6-(3-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxideare suspended in 100 ml. of methylene chloride and 100 ml. of water. Thesuspension is adjusted with concentrated sodium hydroxide to pH 12.7.The mixture is stirred for 1 hour, the two phases are then separated andthe aqueous phase is adjusted to pH 3 with concentrated hydrochloricacid, a white precipitate separating out. This precipitate is filteredoff and recrystallized from a mixture of methylene chloride andmethanol, there being obtained pure methylracemic-5-(3-hydroxy-1-piperidinyl)-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate,having a melting point of 244°-247° C. (decomposition).

The starting material can be prepared as follows:

A suspension of 5.2 g. of dimethyl6-chloro-2,4-pyrimidine-dicarbamate-3-oxide in 300 ml. of methylenechloride is treated with 12.4 g. of 3-hydroxy-piperidine and stirred for60 hours under an argon atmosphere. The residue is then filtered off andthe filtrate is concentrated, a white precipitate separating out. Thisprecipitate is filtered off and recrystallized from a mixture ofmethylene chloride and methanol, there being obtained pure dimethylracemic-6-(3-hydroxy-1-piperidinyl)-2,4-pyrimidine-dicarbamate-3-oxide,having a melting point of 255° C. (decomposition).

The following Examples illustrate pharmaceutical preparations containingthe oxadiazolopyrimidine derivatives provided by the present invention:

EXAMPLE A

Tablets containing the following ingredients are prepared:

    ______________________________________                                                   Butyl 5-piperidino-2-oxo-2H-[1,2,4]-oxa-                                      diazolo[2,3-a]pyrimidine-7-carbamate                               I          (micronized)            20.0 mg.                                              Lactose (powdered)      40.0 mg.                                              Maize starch (white)    24.9 mg.                                              Dioctyl sodium sulfosuccinate                                                                         0.1 mg.                                    II         Maize starch (white)    5.0 mg.                                               Water                   q.s.                                       III        Maize starch (white)    6.0 mg.                                               Talc                    3.0 mg.                                    IV         Magnesium stearate      1.0 mg.                                                                       100.0 mg.                                  ______________________________________                                    

The ingredients of phase I are sieved and mixed. This mixture ismoistened with the maize starch paste, phase II, and kneaded. The moistmass is granulated, dried and converted into a suitable granular size.Phase III is admixed. The resulting mixture is mixed with phase IV for afurther short time. The ready-to-press mixture is pressed to tabletsweighing 100 mg., having a diameter of 7 mm. and having a break-bar.

EXAMPLE B

Tablets containing the following ingredients are prepared:

    ______________________________________                                                  Butyl 5-piperidino-2-oxo-2H-[1,2,4]-oxa-                                      diazolo[2,3-a]pyrimidine-7-carbamate                                I         (micronized)             200.0 mg.                                            Lactose (powdered)       42.9 mg.                                             Maize starch (white)     50.0 mg.                                             Dioctyl sodium sulfosuccinate                                                                          0.1 mg.                                    II        Maize starch (white)     20.0 mg.                                             Water                    q.s.                                       III       Maize starch (white)     30.0 mg.                                             Talc                     3.5 mg.                                    IV        Magnesium stearate       3.5 mg.                                                                       350.0 mg.                                  ______________________________________                                    

The ingredients of phase I are sieved and mixed. This mixture ismoistened with the maize starch paste, phase II, and kneaded. The moistmass is granulated, dried and converted into a suitable granular size.Phase III is admixed. The resulting mixture is mixed with phase IV for afurther short time. The ready-to-press mixture is pressed to tabletsweighing 350 mg., having a diameter of 11 mm and having a break-bar.

EXAMPLE C

Capsules containing the following ingredients are prepared:

    ______________________________________                                                  Butyl 5-piperidino-2-oxo-2H-[1,2,4]-oxa-                                      diazolo[2,3-a]pyrimidine-7-carbamate                                I         (micronized)             20.0 mg.                                             Lactose (powdered)       48.0 mg.                                             Maize starch             5.0 mg.                                    II        Water                    q.s.                                                 Lactose (crystalline)    50.0 mg.                                   III       Maize starch             15.0 mg.                                             Talc                     10.0 mg.                                   IV        Magnesium stearate       2.0 mg.                                                                       150.0 mg.                                  ______________________________________                                    

The ingredients of phase I are sieved and mixed. The mixture ismoistened with the maize starch paste, phase II, and kneaded. The moistmass is granulated, dried and converted into a suitable granular size.Phase III is admixed. The resulting mixture is mixed with phase IV for afurther short time. The mixture is filled into capsules (size 2) eachcontaining 150 mg.

EXAMPLE D

Capsules containing the following ingredients are prepared:

    ______________________________________                                                  Butyl 5-piperidino-2-oxo-2H-[1,2,4]-oxa-                                      diazolo[2,3-a]pyrimidine-7-carbamate                                I         (micronized)             200.0 mg.                                            Lactose (powdered)       50.0 mg.                                             Maize starch             15.0 mg.                                   II        Water                    q.s.                                                 Lactose (crystalline)    50.0 mg.                                   III       Maize starch             20.0 mg.                                             Talc                     10.0 mg.                                   IV        Magnesium stearate       5.0 mg.                                                                       350.0 mg.                                  ______________________________________                                    

The ingredients of phase I are sieved and mixed. The mixture ismoistened with the maize starch paste, phase II, and kneaded. The moistmass is granulated, dried and converted into a suitable granular size.Phase III is admixed. The resulting mixture is mixed with phase IV for afurther short time. The mixture is filled into capsules (size 1) eachcontaining 350 mg.

EXAMPLE E

An aqueous drop suspension containing the following ingredients isprepared:

    ______________________________________                                                              10 mg. per 1 ml.                                        ______________________________________                                        Butyl 5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo-                                 [2,3-a]pyrimidine-7-carbamate (micronized)                                                             0.1 g.                                              Sodium benzoate           0.035 g.                                            Sodium saccharin          0.015 g.                                            Acrylic acid polymerizate 0.1-1.0 g.                                          Saccharose                3.5 g.                                              Citric acid               0.025 g.                                            Polyoxyethylene stearate  0.002-0.01 g.                                       Sodium hydroxide          q.s.                                                Aroma                     q.s.                                                Foodstuff colorant        q.s.                                                Deionized water           ad 10.0 ml.                                         ______________________________________                                    

EXAMPLE F

An aqueous drop suspension containing the following ingredients isprepared:

    ______________________________________                                                            100 mg. per 1 ml.                                         ______________________________________                                        Butyl 5-piperidino-2-oxo-2H-[1,2,4]                                            oxadiazolo[2,3-a]-                                                            pyrimidine-7-carbamate (micronized)                                                                  1.0 g.                                                Sodium benzoate         0.035 g.                                              Sodium saccharin        0.015 g.                                              Acrylic acid polymerizate                                                                             0.05-0.5 g.                                           Saccharose              3.5 g.                                                Citric acid             0.025 g.                                              Polyoxyethylene stearate                                                                              0.002-0.01 g.                                         Sodium hydroxide        q.s.                                                  Aroma                   q.s.                                                  Foodstuff colorant      q.s.                                                  Deionized water         ad 10.0 ml.                                           ______________________________________                                    

We claim:
 1. A compound of the formula ##STR10## wherein R" ishaloalkyl, aralkyl or aryl.